BACKGROUND: Genetic variants in desmosomal cadherins, desmoglein 2 ( DSG2 ) and desmocollin 2 ( DSC2 ), cause a distinct form of arrhythmogenic right ventricular cardiomyopathy (ARVC), which remains poorly reported. In this study, we aimed to provide a comprehensive description of the phenotypic expression, natural history, and clinical outcomes of patients with this ARVC subset. METHODS: Genetic and clinical data of DSG2 and DSC2 variant carriers were collected from 5 countries in Europe and Asia. We assessed the phenotypic profile of these patients and their clinical outcomes, focusing on heart failure and ventricular arrhythmia events. RESULTS: Overall, 271 subjects, 254 with DSG2 variants, were included in this study (median age, 38 years [interquartile range, 25–52]; 62.7% male). Of these, 165 were probands, and 200 were diagnosed with definite ARVC. A total of 181 (66.8%) individuals carried missense variants, mainly distributed in the extracellular domains. Notably, we included 78 (28.8%) individuals with multiple variants. Of the 200 cases with diagnosed ARVC, 41 (20.5%) experienced premature cardiac death before the age of 65. Among the 81 individuals for whom both left ventricular ejection fraction and right ventricular fractional area change data were available at presentation, 29 (35.8%) had isolated right ventricular dysfunction, and 16 (19.8%) had biventricular dysfunction. Single-variant carriers who engaged in intense physical exercise were younger at disease onset compared with those who did not ( P =0.001). Compared with single-variant carriers, those with multiple variants were more likely to be diagnosed with ARVC (96.2% versus 64.8%; P <0.001) and exhibited more severe left ventricular dysfunction (44.4% versus 22.1%; P =0.001) and right ventricular dilation (88.9% versus 55.8%, P <0.001). Multiple-variant carriers were significantly younger at ARVC diagnosis compared with single-variant carriers (33 [18–49] years versus 42 [27–54] years; P <0.001]. During follow-up, end-stage heart failure ( P <0.001) and malignant ventricular arrhythmias ( P =0.004) were significantly more frequent in multiple-variant compared with single-variant carriers. Compared with PKP2 patients, DSG2/DSC2 patients exhibited a significantly higher risk of end-stage heart failure ( P <0.001). CONCLUSIONS: ARVC attributable to variants in desmosomal cadherins mostly present with right ventricular or biventricular disease. Multiple variants are common in these patients and are associated with more frequent clinical penetrance, earlier onset of disease, and adverse clinical outcomes.

Aortic stenosis (AS) is the most prevalent valvular heart disease in Europe and North America, with transcatheter aortic valve implantation (TAVI) revolutionizing its management. Hypertrophic left ventricle (HLV) frequently coexists with AS, complicating treatment due to the associated risk of left ventricular outflow tract (LVOT) obstruction, heart failure, and sudden death. A rare but severe post-aortic valve replacement (AVR) complication, termed “suicide left ventricle” (SLV), has emerged, necessitating further study. This report synthesizes current literature on SLV, its pathophysiology, and management strategies, alongside four patient case studies. The patients aged 79–87 years, underwent AVR for symptomatic AS with HLV. Post-AVR, all experienced severe complications, including dynamicLVOT gradients, systolic anterior motion (SAM) of the mitral valve, and severe hypotension, leading to death in two cases. One patient survived following surgical aortic valve replacement (SAVR) with surgical myectomy. One patient survived after TAVI. These cases highlight the critical importance of multidisciplinary Heart Team evaluations and personalized treatment plans in managing SLV. Despite advancements in AVR, SLV remains a complex, life-threatening condition, requiring an exhaustive and multifaceted approach for optimal patient outcomes. This report offers valuable insights into SLV occurrence and management from a clinical perspective.

Heart failure (HF) remains a critical global health challenge, necessitating advancements in diagnostic and therapeutic strategies. This review explores the evolution of imaging technologies and their impact on HF management, focusing on three-dimensional echocardiography (3DE), myocardial strain imaging, and vortex dynamics imaging. Three-dimensional echocardiography enhances traditional echocardiography by providing more accurate assessments of cardiac structures, while myocardial strain imaging offers the early detection of subclinical myocardial dysfunction, crucial in conditions such as chemotherapy-induced cardiotoxicity and ischemic heart disease. Vortex dynamics imaging, a novel technique, provides insights into intracardiac flow patterns, aiding in the evaluation of left ventricular function, valve diseases, and congenital heart anomalies. The integration of these advanced imaging modalities into clinical practice facilitates personalized treatment strategies, enabling the earlier diagnosis and more precise monitoring of disease progression. The ongoing refinement of these imaging techniques holds promise for improving patient outcomes and advancing the field of precision medicine in HF care.

Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and heart transplantation (HTx), with genetic factors playing a significant role. In recent years, the RNA-binding protein motif 20 (RBM20), which affects the gene splicing of various proteins with different cellular functions, was identified as the first DCM gene with regulatory properties. Variants of RBM20 have been associated with severe forms of DCM. The aim of this critical systematic review was to analyse RBM20 cardiomyopathy clinical features and outcomes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: “RBM20”; “cardiomyopathy”; “arrhythmias”; “heart failure”. A total of 181 records were screened, of which 27 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, eight papers reporting 398 patients with RBM20 pathogenic variants were analysed. The mean age at presentation was 41 years. Familiarity with cardiomyopathy was available in 59% of cases, with 55% of probands reporting a positive family history. Imaging data indicated a mild reduction of left ventricular ejection fraction (mean LVEF 40%), while tissue characterization was reported in 24.3% of cases, showing late gadolinium enhancement in 33% of patients. Composite outcomes of sustained monomorphic ventricular tachycardia or ventricular fibrillation occurred in 19.4% of patients, with 12% undergoing HTx. There were no gender differences in arrhythmic outcomes, while 96.4% of patients who underwent HTx were male. In conclusion, RBM20 cardiomyopathy exhibits a severe phenotypic expression, both in terms of arrhythmic burden and HF progression.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder characterized by structural and functional myocardial alterations, often accompanied by ventricular arrhythmias (VAs), which may ultimately result in sudden cardiac death (SCD). While mutations in genes coding for desmosomal components are commonly identified in affected individuals, genetic variants involving non-desmosomal proteins have recently been recognized as contributors to the disease’s etiology. In 2008, a mutation in the transmembrane protein 43 (TMEM43) was identified as being responsible for a fully penetrant, sex-related, and severe form of ACM. This review aimed to systematically synthesize the current evidence on the natural history, electrocardiographic, and imaging findings as well as the clinical outcomes of TMEM43 cardiomyopathy. Methods: A systematic search was performed in the PubMed, Scopus, and Web of Science databases, following the PRISMA guidelines, using the terms “TMEM43” AND “cardiomyopathy”. After an initial screening of 144 retrieved articles, 80 were considered relevant. Upon a full-text review and eligibility assessment, 12 studies involving 903 individuals harboring TMEM43 variants were selected for inclusion. Results: Male patients more frequently carried the pathogenic TMEM43 variant (n = 505, 55.9%) and exhibited an earlier arrhythmic onset of the disease (33.2 years old versus 46.2 years old in female patients), supporting the need for earlier implantable cardioverter–defibrillator implantation (30.4 versus 42.2 years old). Palpitations, chest pain, and syncope were the most common presenting symptoms. Baseline electrocardiograms commonly demonstrated poor R wave progression, QRS prolongation, and premature ventricular contractions (PVCs). Arrhythmic events, including malignant VAs and SCD, were early manifestations of the disease, especially in male patients. Frequent PVCs and left ventricular dilation were considered early markers of the disease and were predictive of arrhythmic events. Conversely, heart failure was reported as a late clinical outcome, requiring heart transplantation in a minority of cases (1.5%). Conclusions:TMEM43 cardiomyopathy is a fully penetrant autosomal dominant form of ACM, characterized by a well-defined clinical phenotype that is more severe and presents earlier in male patients.

Background: Desmosomal “hot‐phase” cardiomyopathy (HPC), characterized by bursts of myocardial inflammation mimicking acute myocarditis (AM), carries relevant risks of adverse outcomes. This study aimed to identify diagnostic “red flags” favoring HPC over AM. Methods: Patients (n=134) receiving a first diagnosis of AM, proven by endomyocardial biopsy or cardiac magnetic resonance plus troponin elevation, were retrospectively identified at a referral center. HPC was defined by presence of pathogenic desmosomal gene variants (DGVs). Clinical, imaging, and electrical features were compared between HPC cases and controls with gene‐negative AM to identify red flags. Diagnostic algorithms were derived and tested in an external multicenter cohort of DGV carriers (n=30). Results: Patients with HPC (n=22; 91% DSP +) were more frequently female (73% versus 24%, P <0.001) and younger than unmatched controls with AM (32±14 versus 41±14 years, P =0.007). When matched 1:1 by age, sex, and presentation, DGV carriers showed distinctive red flags: family history of cardiomyopathy/AM/sudden death; recurrent troponin peaks; persistent left ventricular systolic dysfunction; right ventricular involvement; ring‐like late gadolinium enhancement; late gadolinium enhancement persistence or extension; low QRS voltages; life‐threatening ventricular arrhythmias at 1000/24 hours ventricular ectopy; and recurrent nonsustained ventricular tachycardia. A “first‐contact” algorithm based on female sex and age <30 years achieved 77% accuracy, identifying 63% of DGV carriers in the external cohort. An alternative algorithm incorporating ring‐like late gadolinium enhancement, right ventricular involvement, and family history showed higher accuracy (93%) and yield (93%). Conclusions: Myocarditis in DGV carriers predominantly affects young women. A red flag‐based approach improves recognition of desmosomal HPC over classic AM.